This invention relates to a method of treating metabolic derangement, characterized by cellular oxidative dysfunction, in living tissue. More particularly, the invention relates to the administration of a cellular oxidative function altering agent while monitoring cellular oxidative function. The agent is administered until cellular oxidative function is restored.
Many clinical states, such as shock, sepsis, heart attacks and strokes, result from ischemia. Ischemia is a condition involving a lack of adequate blood flow to vital organs and tissues. Similarly, patients undergoing surgical procedures can suffer from a lack of adequate blood flow and thus, ischemia. Ischemia and subsequent reperfusion leads to depletion of high energy stores and impaired mechanical function of the affected organs and tissues. Ferrarri, J. Cardiovasc. Pharmacol., 28 (suppl 1), S1 (1996). The extent and severity of the damage depends on a number of factors including the nature of the ischemic event and the health of the tissue prior to the event.
The major metabolic system in humans is the mitochondrial oxidative phosphorylation system. Over 90% of the oxygen available to the cell is utilized for this system, which uses oxygen to transform the energy equivalents of substrates, including substances such as sugars, proteins and fats to energy molecules of use to the cell, i.e., adenosine triphosphate (ATP). Mitochondrial oxidative phosphorylation is thus central to the restoration of high energy stores and mechanical function after an ischemic event. However, key mitochondrial enzyme systems show partial inhibition after periods of ischemia and reperfusion. Id.
Current therapies directed at reversing the effects of ischemia and reperfusion involve restoring blood flow and oxygen to the affected organs and tissues. However, cellular oxidative dysfunction can persist even after blood flow and oxygen is restored. Thus, these therapies, although effective for resuscitation purposes, may not result in the fully functional recovery of the affected cells and tissue. Furthermore, although therapies have been proposed that involve the administration of basic cellular substrates (e.g., glucose) for the purpose of restoring cellular oxidative metabolism to a functional state, these therapies have been undirected. Thus, there is a need for a direct, noninvasive, efficacious method of restoring cellular oxidative function to tissues and organs after periods of ischemia and reperfusion.
The present invention is a method for treating metabolic derangement in living tissue, characterized by cellular oxidative dysfunction, by administering an amount of an agent to alter cellular oxidative function, while monitoring cellular oxidative function. In this manner, the present invention provides a direct, noninvasive method for the treatment of conditions characterized by metabolic derangement.
As used herein, the phrase xe2x80x9cmetabolic derangementxe2x80x9d is meant to indicate a state of cellular oxidative dysfunction. In a preferred sense, the phrase xe2x80x9cmetabolic derangementxe2x80x9d is meant to indicate a condition wherein the relationship between tissue oxygen availability and mitochondrial oxygen utilization is decoupled. The relationship between tissue oxygen availability and mitochondrial oxygen utilization may become decoupled in response to a variety of external stimuli or conditions, including, but not limited to, poisoning, stroke, heart attack, sepsis, low blood pressure or as a result of surgery. Thus, the method of the present invention will be suitable for the treatment of these diseases or conditions, as well as any others that occur either as a result of, or have as a result, metabolic derangement.
The present invention represents an improvement in treating metabolic derangement in living tissue. Specifically, Applicants have discovered that, by monitoring cellular oxidative function, e.g., the coupling relationship between mitochondrial oxygen utilization and tissue oxygen availability to assess the level of coupling, and by utilizing this assessment to direct the administration of agents to alter this function and/or relationship, cellular oxidative dysfunction can be restored to a functional state. Applicants have also found evidence of metabolic derangement following periods of ischemia in both experimental models (rat hearts) and in human patients suffering shock after severe traumatic injury. In both instances, the method of the present invention was effective to restore cellular oxidative function.
Generally, the present invention provides a method of treating metabolic derangement in living tissue using cellular oxidative function as a treatment indicator. That is, the cellular oxidative function altering agent is administered until an appropriate change in cellular oxidative function is detected. In this manner, the present invention provides a method of treating metabolic derangement by optimizing cellular oxidative function. More specifically, the present invention provides a method of treating metabolic derangement in living tissue comprising the steps of administering a cellular oxidative function altering agent while monitoring cellular oxidative function. The administration of the agent is preferably altered as needed as a function of the cellular oxidative function and, when cellular oxidative function is restored, the administration of the agent is preferably ceased.
In a preferred embodiment, cellular oxidative function is assessed by monitoring tissue oxygen availability and mitochondrial oxygen utilization and determining the coupling relationship between tissue oxygen availability and mitochondrial oxygen utilization. If it is determined that tissue oxygen availability and mitochondrial oxygen utilization are xe2x80x9cdecoupled,xe2x80x9d the cellular oxidative function altering agent is administered until such time that it is determined that the tissue oxygen availability and mitochondrial oxygen utilization have been restored to a coupled relationship.
Preferably the living tissue will be a blood-containing tissue, which shall be understood to include any tissue perfused with blood, or even blood itself, which is also a tissue. The present invention is not so limited however, and it will be readily apparent to those of skill in the art that the present inventive method is also useful for treating non-blood perfused tissue when it is desirable to do so.